1. Field of the Invention
This invention relates to a process for the preparation of .alpha.-aspartyl-L-phenylalanine methyl ester having low hygroscopicity and excellent storage stability.
2. Related Art
.alpha.-L-aspartyl-L-phenylalanine methyl ester (hereinafter abbreviated as ".alpha.-APM") is a substance useful as a sweetening agent. It is nearly 200 times as sweet as sucrose and moreover, its sweet taste resembles that of sugar. For these reasons, its demand is growing these days as a dietary sweetening agent.
.alpha.-APM is known to have either one of two crystalline forms having different hygroscopicity, namely, form I and form II. The crystalline form I has high hygroscopicity so that the water content at equilibrium may reach as high as 10 percent. In contrast, the crystalline form II has low hygroscopicity and the water content is as low as about 3 percent at equilibrium (U.S. Pat. No. 4,579,747).
When .alpha.-APM of the crystalline form I is provided as a final product, its water content increases due to its high hygroscopicity after its production until its shipping so that it tends to become an off-specification product (the water content of .alpha.-APM is specified to be 4.5% max. in the Japanese Standard for Food Additives). It is hence necessary to pay special attention to the storage of products. Even when formed together with one of various vehicles into a sweetener in the form of either granules or tablets, the sweetener may undergo browning In the case of granules, it is known that the flowability of the granules tends to drop on storage In the case of tablets on the other hand, the readiness of their disintegration upon addition to water is known to have tendency to deteriorate in the course of their storage The thus-reduced flowability and disintegration readiness are known to lead to a reduction in solubility.
When .alpha.-APM is provided as a final product of the crystalline form II on the other hand, such troubles seldom occur. It is hence desired to prepare .alpha.-APM in the crystalline form II and to formulate it into a final product in the same crystalline form.
As processes for the preparation of .alpha.-APM, a variety of processes have already been disclosed, centering on chemical processes. Various preparation processes have been known including, for example, to subject an N-protected-L-aspartic anhydride and L-phenylalanine methyl ester to condensation and then to deprotect the resultant N-protected-.alpha.-L-aspartyl-L-phenylalanine methyl ester or to esterify N-formyl-.alpha.-L-aspartyl-L-phenylalanine, which has been obtained by condensing N-formyl-L-aspartic anhydride and L-phenylalanine, or its deformylation product, i.e., .alpha.-L-aspartyl-L-phenylalanine in a medium composed of hydrochloric acid and methanol Whichever process is employed, .alpha.-APM is processed and/or treated into a final product by conducting its purification such as recrystallization. It is however usual to subject .alpha.-APM to purification such as recrystallization from water or a mixed solvent of an alcohol and water and then to dry the thus-purified crystals into a final product, since .alpha.-APM is either insoluble or hardly soluble in organic solvents However, .alpha.-APM crystals obtained by such purification generally have the crystalline form I and are hence high in hygroscopicity and poor in storage stability.
Regarding the preparation of II-form crystals having low hygroscopicity, only one process has been known in which form-I crystals obtained by a conventional process are dried at a temperature of 80.degree. C or higher so as to convert their crystalline form from I to II (U.S. Pat. No. 4,579,747).
.alpha.-APM is however susceptible to an intramolecular cyclizing reaction as readily envisaged from its structure, so that it tends to be converted into a diketopiperazine compound (5-benzyl-3,6-dioxopiperazine-2-acetic acid) having no sweet taste Accordingly, the product specification rules the tolerable maximum content of the above compound (The tolerable content of the above compound in .alpha.-APM is specified to be 1.5 percent max. according to the Japanese Standard for Food Additives). Since .alpha.-APM is dried at an elevated temperature of 80.degree. C. or higher in the known process described above, the byproduction of an undesirable compound, i.e., the above-described diketopiperazine compound tends to occur. As a result, reprocessing may be indispensable in some instances so as to lower the content of the above compound below the value specified for the product.
Incidentally, the present inventors reproduced Preparation Example 1 described in the U.S. patent specification referred to above, namely, dried at 90.degree. C. and under reduced pressure crystals of .alpha.-APM which had been obtained by conducting filtration and water-washing subsequent to the neutralization of .alpha.-APM hydrochloride with a 10 percent aqueous solution of sodium carbonate in water. As a result, the thus-obtained .alpha.-APM was certainly found to have the crystalline form II from its X-ray diffraction spectrum Upon analysis of the content of the diketopiperazine compound, .alpha.-APM was however found to contain it in an amount as much as 2.3 percent. This data is apparently higher than the tolerable maximum level specified for the diketopiperazine compound
As demonstrated by the above experiment of the present inventors, the process in which .alpha.-APM is dried under temperature conditions of 80.degree. C. or higher tends to induce byproduction of one or more undesirable compounds and is thus not considered to be a preferable process from the industrial viewpoint.
It is essential to reduce the drying temperature substantially in order to minimize or inhibit the byproduction of the diketopiperazine compound It has accordingly been desired to develop a process which can provide II-form crystals by drying .alpha.-APM at a relatively low temperature.